tbuckley/cabot-search huggingface dataset:
Abstract 134: Lymph node metastases are seeded via two distinct ways in phylogenetic study of gastric cancer
Authors: Pei-Chi Cheng, Wei-Ting Hung, Yung-Ming Jeng, I-Rue Lai
Journal: Cancer Research (2023)

Abstract Backgrounds: Gastric cancer (GC) ranked 5th and 8th on the list of cancer related deaths worldwide and in Taiwan, respectively. Due to its high frequency of lymph node spread, lymph node dissection has become a standard procedure in surgical treatment. A randomized trial showed that patients who underwent D2 lymphadenectomy had a better 5-year survival outcome than ones who had D1 dissection in advanced gastric cancer, implying the D2 lymph node might serve as an outpost before tumor cells spread to distant organs. This clinical observation raises a possibility that the regional lymphatic spread could be under strict selection but not a passive process. Materials and Methods: To understand the evolutionary relationship between primary tumors, perigastric lymph nodes, and second tier of lymph nodes in the extra-perigastric area, we reconstruct their phylogeny using genetic variants in hypermutable DNA regions where the mutation rate is 102~104-fold than unique sequence. We have assembled a cohort of 10 gastric cancer patients, including intestinal-, diffuse- and mixed type GC. For each case, we collected all workable lymph node metastases and intensely sampled primary tumors. On average, we have over fifteen samples per case on the phylogenetic tree. Results: Preliminary data of the first two patients show high heterogeneity within primary tumors as well as between different lesions of lymph nodes or peritoneal metastases in gastric cancer. Interestingly, in stark contrast to all other lymph node metastases which intermingle with primary tumors, a clade consisting of one proximal and one distal lymph node with a bootstrap value above 90% is observed in each phylogeny, and it is worth noting that samples on these clades are from intestinal type tumor. Conclusion: Our results indicate that most tumor cells arrive both regional and distal lymph nodes passively via lymphatic drainage in GC while a selective process also exists which coincides with clinical observation. Whether the existence of tumor cells under a relatively stricter selection process would lead to different clinical outcomes is under investigation. Citation Format: Pei-Chi Cheng, Wei-Ting Hung, Yung-Ming Jeng, I-Rue Lai. Lymph node metastases are seeded via two distinct ways in phylogenetic study of gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 134.
Abstract 4885: APR-246 cytotoxic effects are TP53 independent in endometrial cancer cell lines
Authors: Camilla Yu, Aaron Petty, Roberto Vargas
Journal: Cancer Research (2023)

Abstract Background: The majority (80%) of endometrial cancer (EC) related mortality is due to high-grade tumor histology, which harbor high rates of TP53 mutations. APR-246 is a small-molecule drug designed to restore WT p53 signaling in TP53-mutant cancers and has yet to be explored in EC. We aimed to test the cytotoxic potential for APR-246 in EC and its downstream impact. Methods: Using 3 parental EC cell lines with differing TP53 statuses, JHUEM2 (WT), Hec108 (hetero P151H), and Hec1B (R248Q), we generated dose-response curves for APR-246. Cells were treated for 24 hours and viability assessed with CellTiter-Glo after 9 days. To assess for mutation specific effect, we generated dose-response curves using a WT non-targeting control (NTC), CRISPR/Cas9 KO of TP53, and five KO cell lines complemented with 5 common TP53 mutations (R248Q, R248W, R273C, R273H, Y220C). Western blot analysis was performed to assess for p53, p21, PUMA, GADD45, and NOXA using whole-cell lysates, after treatment with 20μM of APR-246 for 24 hours. To further evaluate for a time-dependent effect, 2 representative variants (R248Q and R273C) after 6 and 24 hours of incubation with 50μM APR-246 and 10μM of Nutlin-3. Results: APR-246 demonstrated a negative, dose-dependent effect on cell viability in all EC cell lines. IC50s for JHUEM2, Hec108, and Hec1B were 2.5μM, 4.3μM, and 4.5μM respectively. For NTC, the IC50 was (1.7μM), while TP53-KO (7.5μM) demonstrated similar IC50 values to the variants (6.5-11.9μM). Two variants (Y220C and R248W), had significantly (&amp;lt;0.001 and &amp;lt;0.01 respectively) higher IC50 values (11.9 and 9.1 μM respectively). In Western blot analysis, no p53 downstream signaling via p21, GADD45, PUMA, and NOXA was observed for any variants. Conclusions: Our results demonstrate that APR-246's cytotoxic effects in EC seem to be p53-independent. Potential mechanisms for the anti-neoplastic effects of APR-246 include activity targeting antioxidant pathways demonstrated in other solid tumors and provides an area for further investigation in TP53mut EC. Citation Format: Camilla Yu, Aaron Petty, Roberto Vargas. APR-246 cytotoxic effects are TP53 independent in endometrial cancer cell lines. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4885.
Abstract 6452: A plasma metabolomic signature of healthy lifestyles and risk of colorectal cancer in the UK Biobank
Authors: Fangcheng Yuan, Danxia Yu, Wanqing Wen, Wei Zheng
Journal: Cancer Research (2023)

Abstract Background: Lifestyle factors contribute to the etiology of colorectal cancer (CRC). We aimed to derive a metabolomic signature of adherence to healthy lifestyles and examine its association with CRC risk. Methods: In the analysis, we included 98,898 UK Biobank participants with 168 metabolomic biomarkers measured by nuclear magnetic resonance spectroscopy from baseline plasma samples. A healthy lifestyle score (HLS) was derived from 8 lifestyle factors according to the American Cancer Society (ACS) guidelines. We applied elastic net regularized regressions to identify a metabolomic signature from 130 biomarkers. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of metabolomic signature with CRC risk after adjusting for known confounders. Results: During a median follow-up time of 8.2 years, 818 incident primary CRC cases were identified after participants were enrolled for more than two years. We observed a strong partial correlation between the metabolomic signature and HLS (r = 0.34), as well as waist-to-hip ratio, sedentary time, red and processed meat intake, and tobacco smoking aspects of the HLS (r = 0.14-0.33). A higher HLS was characterized by a signature of increased levels of linoleic acid, total cholines, and polyunsaturated fatty acids and decreased levels of omega-6 fatty acids, phospholipids in intermediate-density lipoprotein, and phosphatidylcholines. The metabolomic signature showed a significantly inverse association with CRC risk (HR = 0.84; 95% CI = 0.80-0.89 per standard deviation increment). The significantly inverse associations were observed irrespective of sex, educational attainment, and CRC subsite. Stronger associations were seen among participants aged between 50 and 60 years at study enrollment, and those diagnosed with CRC at 60 years old or later. Conclusion: We identified a metabolomic signature characterizing adherence to the ACS guidelines and showed that the signature was inversely associated with CRC risk. Citation Format: Fangcheng Yuan, Danxia Yu, Wanqing Wen, Wei Zheng. A plasma metabolomic signature of healthy lifestyles and risk of colorectal cancer in the UK Biobank [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6452.
Abstract 1124: PTEN loss confers resistance to anti-PD-1 therapy in NSCLC by increasing tumor infiltration of T regulatory cells
Authors: Francisco Exposito, Miriam Redrado, Maeva Houry, Katherine Hastings, Magdalena Molero-Abraham, Teresa Lozano, Jose L. Solorzano, Julian Sanz Ortega, Vera Andradas, Ramon Amat, Esther Redin, Sergio Leon, Naroa Legarra, Javier García, Diego Serrano, Karmele Valencia, Camila Robles-Oteiza, Giorgia Foggetti, Enriqueta Felip, Juan J. Lasarte, Luis Paz-Ares, Jon Zugazagoitia, Katerina Politi, Luis M Montuenga, Alfonso Calvo
Journal: Cancer Research (2023)

Abstract Immune checkpoint inhibitors (ICIs) targeting PD-L1/PD-1 have dramatically improved the management of NSCLC patients. Nevertheless, more than 50% patients will present primary resistance or will develop secondary resistance within 12-25 months after treatment initiation. The mechanisms of resistance to ICIs may depend on tumor-intrinsic molecular/genetic alterations that generate an immunosuppressive tumor microenvironment (isTME). Using In silico analyses (TCGA and AACR-GENIE cohorts), and protein expression analysis in our institutional CIMA-CUN cohort, we have shown that &amp;gt;50% LUSC and ~28% LUAD tumors exhibited reduced PTEN mRNA/protein levels. Patients with PTEN-low tumors had higher levels of CXCL10, PD-L1 and PD-L2. In a cohort of stage IV NSCLC patients treated with ICIs, we found that patients with low tumor PTEN levels were significantly associated with worse OS (p=0.021). We have developed and characterized a Pten-null LUSC model using UN680 cells, which was also refractory to anti-PD-1 when implanted in syngeneic mice. Pten loss led to a deregulation of multiple pathways related to immunosuppression, with a positive enrichment in “IL-6/JAK/STAT3” and “TNF-α via NFkB” hallmarks, identified by GSEA. Tumors from the Pten-null LUSC model were highly metastatic and fibrotic, and secreted TGF-β/CXCL10, thus favoring conversion of CD4+ lymphocytes into Tregs. Human/mouse PTEN-low tumors were enriched in Tregs and immunosuppressive genes. Importantly, treatment of mice bearing Pten-null tumors with TLR agonists+anti-TGF-β, aimed to alter this isTME, led to tumor rejection and immunological memory in 100% of mice. Our results demonstrate that lack of PTEN causes immunotherapy resistance in LUSC by establishing an isTME that can be reversed therapeutically. Citation Format: Francisco Exposito, Miriam Redrado, Maeva Houry, Katherine Hastings, Magdalena Molero-Abraham, Teresa Lozano, Jose L. Solorzano, Julian Sanz Ortega, Vera Andradas, Ramon Amat, Esther Redin, Sergio Leon, Naroa Legarra, Javier García, Diego Serrano, Karmele Valencia, Camila Robles-Oteiza, Giorgia Foggetti, Enriqueta Felip, Juan J. Lasarte, Luis Paz-Ares, Jon Zugazagoitia, Katerina Politi, Luis M Montuenga, Alfonso Calvo. PTEN loss confers resistance to anti-PD-1 therapy in NSCLC by increasing tumor infiltration of T regulatory cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1124.
Abstract 1709: MAPK pathway alterations are a targetable vulnerability in bladder cancer
Authors: Raie Bekele, Amruta Samant, Timothy Hanlon, Kent Mouw
Journal: Cancer Research (2023)

Abstract Bladder cancer (BC) is the fourth most common cancer in males and accounts for about 80,000 new cases in the US. Approximately 25% patients with BC will present with muscle-invasive bladder cancer (MIBC) and for the past several decades the standard-of-care for MIBC and metastatic bladder cancer has been cisplatin-based chemotherapy. More recently, multiple immunotherapeutic agents have been approved but only a subset of patients respond to these treatments and therefore novel therapeutic strategies are needed to expand treatment options and improve clinical outcomes for BC patients. Large-scale genomic studies of MIBC have identified numerous recurrent genomic alterations including mutations, copy number alterations, and chromosomal translocations. Using publicly available patient datasets, we identified ~20% of MIBC patients harboring alterations in genes involved in the mitogen-activated protein kinase (MAPK) pathway and their upstream activators. RAF1 copy number amplification was the most predominant alteration followed by activating HRAS mutations. Leveraging our institutional cohorts of bladder cancer specimens, we defined the frequency of these alterations and validated RAF1 amplification in a subset of cases using fluorescence in situ hybridization. To functionally define the role of MAPK pathway alterations in BC, we tested activity of RAF and MEK inhibitors in BC cell line models with diverse MAPK pathway alterations including RAF1 amplification and HRAS/NRAS mutations. We found that these MAPK pathway altered models displayed increased sensitivity to RAF/MEK inhibition compared to MAPK-unaltered models. We further demonstrated the feasibility of preclinically targeting these alterations in mouse models of BC using cell line and patient-derived-xenografts. Additionally, we tested the impact of MAPK pathway modulation on tumor extrinsic properties including changes in the tumor microenvironment that could potentially affect responses to immunotherapeutic agents. Taken together, we have identified MAPK pathway alterations as a novel dependency in BC that can be targeted with emerging RAF inhibitors. Citation Format: Raie Bekele, Amruta Samant, Timothy Hanlon, Kent Mouw. MAPK pathway alterations are a targetable vulnerability in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1709.
Alliance A021806: A phase III trial evaluating perioperative versus adjuvant therapy for resectable pancreatic cancer.
Authors: Akhil Chawla, Qian Shi, Andrew H. Ko, Shaalan Beg, Anna M. Varghese, Stephen W Behrman, Mark Bloomston, Firas Salem Ahmed, Wendy L. Frankel, Jesse G. Dixon, Xiomara W. Carrero, Ardaman Shergill, Jamie Crawley, Oguz Akin, Daniel John Renouf, George Zogopoulos, Joleen M. Hubbard, Jeffrey A. Meyerhardt, Eileen Mary O'Reilly, Cristina R. Ferrone
Journal: Journal of Clinical Oncology (2023)

TPS4204 Background: The role of neoadjuvant chemotherapy in resectable pancreatic cancer has yet to be defined. Recent phase II trial results demonstrate a median overall survival time (mOS) of only 22.4 months after treatment with perioperative modified FOLFIRINOX (mFOLFIRINOX) with 36% not reaching surgery due to disease progression during neoadjuvant therapy. While potential benefits and shortcomings of neoadjuvant chemotherapy have been well documented, to date, no phase III trial has directly compared a perioperative versus an adjuvant chemotherapy strategy in resectable pancreatic cancer. Alliance for Clinical Trials in Oncology A021806 is an actively accruing randomized controlled phase III trial evaluating the efficacy of perioperative chemotherapy with mFOLFIRINOX in patients with resectable pancreatic cancer. Methods: To qualify for enrollment, patients must have biopsy-proven localized resectable pancreatic adenocarcinoma as defined by the National Comprehensive Cancer Network. Patients must have good performance status (ECOG 0 or 1) and be candidates to receive mFOLFIRINOX treatment. All patients enrolled undergo central radiologic eligibility review for quality control and are then randomized to either Arm 1 which consists of 8 cycles of neoadjuvant mFOLFIRINOX followed by 4 cycles of adjuvant mFOLFIRINOX or Arm 2 which includes upfront surgery followed by 12 cycles of adjuvant mFOLFIRINOX. The primary endpoint of the trial is overall survival with secondary endpoints evaluating disease-free survival, margin-negative resection rate, surgical complications, and chemotherapeutic adverse events. Additional correlative endpoints include quality of life and radiomic imaging assessments. A total enrollment of 352 patients is planned from the US and Canada; current enrollment for this trial is at 145 patients. An OS interim analysis will be performed when 50% of the events (124) are observed combining the two arms. If the trial continues after interim analysis, the final OS analysis will be performed with a total of 248 events (combined arms). If the Cox model (stratified by tumor location and ECOG PS) comparing OS between arms produces a one-sided p-value &lt; 0.05, then we will conclude that the OS of the perioperative therapy arm is superior to adjuvant therapy. The Alliance A021806 phase III trial aims to define a new standard of care for patients with resectable pancreatic cancer. Clinical trial information: NCT04340141 .
Abstract 6341: Preclinical development of a monoclonal antibody targeting CD70 as cancer immunotherapy
Authors: Wenzhi Tian, Song Li, Dianze Chen, Dandan Liu, Huiqin Guo, Chunmei Yang, Li Zhang, Wei Zhang, Xiaoping Tu, Liang Peng, Gui Zhao, Ruliang Zhang, Fan Zhang, Frank X. Gan
Journal: Cancer Research (2023)

Abstract CD70 is a novel immune checkpoint highly expressed on cancers of kidney, blood and lymphoid tissues, mesothelium and gastrointestinal system. High expression of CD70 is a prognostic marker for poor survival in patients with ovarian carcinoma, pancreatic cancer and mesothelioma, etc. Several CD70 antibodies are under early stages of clinical trials for oncology indications. We have developed IMM40H, a humanized IgG1 antibody that differentially induces phagocytosis and cytotoxicity in CD70-expressing cancer cells. Results of in vitro study have demonstrated that, in comparison with cusatuzumab, IMM40H possesses better CD70 binding (kD= 3.22E-11M) and functional inhibition ability, as well as more potent activities of ADCC (antibody-dependent cellular cytotoxicity, EC50 = 0.5 -2.0ng/ml) and CDC (complement-dependent cytotoxicity, EC50 = 170 ng/mL) against certain cancer cells. IMM40H also induces strong ADCP (antibody-dependent cellular phagocytosis) activity (EC50 = 0.02nM). At doses between 0.3 mg/kg to 10mg/kg, IMM40H significantly reduced tumor volume in mouse models of multiple myeloma, lymphoma and kidney cancer. Notably, in a U266 multiple myeloma model, IMM40H, at the dose of 0.3 mg/kg, completely inhibited tumor growth in a way that therapeutic effects appeared significantly earlier than that of cusatuzumab at a higher dose of 1 mg/kg. Therapeutic effects of IMM40H at the dose of 3 mg/kg also appeared earlier than that of bortezomib at the dose of 0.5 mg/kg. Interestingly, combination of IMM40H and IMM01 (a SIRPα-IgG1 Fc fusion protein targeting CD47) generated significant therapeutic synergy in models of A498 kidney cancer and Raji lymphoma. Importantly, maximum tolerated dose of IMM40H exceeds 100 mg/kg (IV, single dose) in cynomolgus monkeys and no significant adverse reaction was observed at a dose range of 3 to 30 mg/kg (IV, QW, 5 times) in monkeys. Taken together, our data show that targeting CD70 on tumor cells using IMM40H antibody may serve as a potent immunotherapy for multiple cancer indications. IND of IMM40H has been approved in China and US. This antibody is now in a phase 1 study in patients with advanced malignancies expressing CD70. Citation Format: Wenzhi Tian, Song Li, Dianze Chen, Dandan Liu, Huiqin Guo, Chunmei Yang, Li Zhang, Wei Zhang, Xiaoping Tu, Liang Peng, Gui Zhao, Ruliang Zhang, Fan Zhang, Frank X. Gan. Preclinical development of a monoclonal antibody targeting CD70 as cancer immunotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6341.
Abstract 1121: Patient-centric Discovery by Active Learning (PeDAL) platform to predict drug response in a heterogeneous patient population
Authors: Robert J. Montgomery, Aaron W. Gilkey, Joshua D. Kangas, Robert F. Murphy, Arlette H. Uihlein
Journal: Cancer Research (2023)

Abstract Even after thorough preclinical testing, only 5% of oncology drug candidates entering clinical trials ultimately get approved for use in patients. To find one drug that will be effective in the clinic, drug developers have to test 20 agents, 19 of which will ultimately prove ineffective. Such high attrition rates drive up the cost of treatment and delay getting effective drugs to the market. Here we describe the Patient-centric Discovery by Active Learning (PeDAL) platform and present results of a study that shows it can predict the effectiveness of a drug or a set of drugs in a patient population with 92% accuracy in only 11 weeks while only performing in vitro assays on a fraction of the drug-patient combinations. The power of PeDAL is derived from a combination of AI technology, an extensive drug response and biomarker database, and a biobank of 150,000 tumor samples from 137 tumor types. The study consists of two phases, the first demonstrates that PeDAL’s predictive model efficiently reveals drug-response patterns that provide insight into the treatment of ovarian cancers. The second phase focuses on the in vitro validation of the accuracy of the predictions. The experimental space was 175 FDA-approved drugs and 130 primary ovarian tumor samples. PeDAL’s active machine learning algorithm iteratively optimizes predictive models by learning from in vitro experiments which take into account tumor-stromal interactions and cellular heterogeneity. Importantly, the ability to model patient-drug combinations across a diverse population of primary samples adds a patient heterogeneity dimension to the generated drug response predictions. After performing 720 high throughput experiments, PeDAL was able to make drug-response predictions for an additional 4,600 drug/tumor predictions. Additional in vitro validation experiments confirm the reproducibility and accuracy of the high-confidence predictions generated by PeDAL with area under the curve (AUC) values &amp;gt;0.95. These results have strong implications not only for the new drug discovery process, but also for identifying opportunities for drug repurposing. We demonstrate that the PeDAL platform is a highly efficient tool to make confident predictions about drug-tumor pairings allowing the discovery of many more drug-tumor responses than are practical to test in vitro. Citation Format: Robert J. Montgomery, Aaron W. Gilkey, Joshua D. Kangas, Robert F. Murphy, Arlette H. Uihlein. Patient-centric Discovery by Active Learning (PeDAL) platform to predict drug response in a heterogeneous patient population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1121.